Amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig's Disease, is a progressive, fatal, neurological disorder characterized by muscle fiber atrophy resulting from the degeneration of motor neurons in the spinal column and brain. ALS affects approximately 30,000 US citizens with only about 10% of the cases being classified as the familial form of ALS. In a subset of familial patients with mutations in the metabolic enzyme superoxide dismutase 1 (SOD1), the pathological progression may be attributed to an unknown gain of function associated with a mutant form of the enzyme (SOD1 dependant) (Rosen, 1993). However in the majority of ALS cases the SOD1 gene contains no mutations, the activity of the SOD1 enzyme is normal, and the mechanism of disease pathology is unknown (SOD1 independent). Therefore the remaining 90% of ALS cases are classified as sporadic cases with no well characterized genetic component or causal agent.
Because the cause of the sporadically occurring form of the disease is unknown, researchers have turned to transgenic strategies to create laboratory models of the disease. Identification role of the SOD1 gene has led to the generation of transgenic rodent models of ALS. A transgenic mouse strain carrying 23 copies of the human SOD1G93A transgene (the “G93A mouse”) is the most widely used murine model of ALS and is accepted as a standard model for ALS therapeutic studies (the “G93A mouse”) (see Tu P H et. al. (1996) Proc Natl Acad Sci USA 93:3155-3160 and Gurney M E (1997) J Neuro Sci 152 Suppl 1: S67-S73)
Although ALS is characterized by loss of motor neurons in the spinal cord resulting in muscle atrophy, the disease also manifests itself with changes in axon transport, protein aggregation, excitotoxicity, astrocytosis, mitochondrial dysfunction, microglial activation, and synaptic remodeling. Microglial activation, astrocytosis and the presence of infiltrating inflammatory cells from the periphery has been well described. There is accumulation of IgG immunoreactive deposits in the spinal cord of ALS patients, infiltration of lymphocytes, dendritic cells, monocytes, and macrophages into the spinal cord in ALS. Although the role of infiltrating immune cells is poorly understood, recent work would suggest that infiltrating T cell populations are neuroprotective and not cytotoxic. Although ALS has an immune component mediated by activation of microglia and astrocytes it is not considered to be an autoimmune disorder. Unlike diseases such as rheumatoid arthritis or systemic lupus erythematosus in which involvement of specific immune modulatory pathways (e.g., the costimulatory pathway) has been described, involvement of such pathways has not been described for ALS.
Currently physicians have limited choices for treating ALS. At this time, riluzole is the only drug that has been approved by the FDA for treatment of ALS. In clinical trials, riluzole has shown only a slight benefit in modestly increasing survival time. Thus there is an urgent need for effective therapies for ALS.